Protein-Protein Interactions in Disease and Pharmacology: Unlocking New Frontiers in Drug Discovery

Proteins constitute the foundational framework of biological systems, executing a vast range of essential functions such as enzymatic catalysis, signal transduction, structural support, and intracellular transport. Within the highly crowded cellular environment, their ability to function effectively over distance is enhanced through the formation of intricate interaction networks, termed interactomes. These networks enable coordinated activity among proteins, allowing them to carry out highly specialized and interdependent biological roles (Nada et al., 2024).

Within these interactomes, protein-protein interactions (PPIs) represent the physical contact points between two or more proteins, typically occurring at domain-specific interfaces. These interactions may be transient or stable, and they govern the dynamic regulation of nearly all biological processes (Scott et al., 2016; Shin et al., 2017). Dysregulation of PPIs is implicated in numerous diseases, including cancer, neurodegenerative disorders, and infectious diseases. Historically, such interfaces were viewed as “undruggable” due to their large, hydrophobic, and relatively flat surfaces that lack the traditional pockets suitable for small-molecule binding (Scott et al., 2016).

However, emerging technologies, including DNA-Encoded Libraries (DELs), are shifting this paradigm. DELs enable the ultra-high-throughput screening of vast chemical spaces for potential binders to protein surfaces previously considered inaccessible (Goodnow et al., 2017; Peterson & Liu, 2023). This innovation is driving renewed momentum in the discovery of therapeutic agents.

PPIs play a critical role in maintaining cellular homeostasis. Disruption or aberrant formation of these interactions can lead to pathological conditions. For instance:

• p53-MDM2 Interaction: MDM2 negatively regulates the tumor suppressor p53. In many cancers, overexpression of MDM2 leads to the inactivation of p53, promoting tumorigenesis (Scott et al., 2016).
• BCL-2 Family Proteins: These proteins regulate apoptosis. Protein-protein interaction inhibitors, targeting the interaction between pro-apoptotic and anti-apoptotic BCL-2 proteins can induce cell death in cancer cells (Kale et al., 2018).
• β-Catenin–TCF Interaction: Dysregulation of this interaction is implicated in colorectal cancer. Targeting this PPI can inhibit Wnt signaling pathways involved in tumor progression (Nada et al., 2024).

An emerging strategy to overcome the challenges of targeting PPIs is targeted protein degradation. This approach involves the use of molecular glues or bifunctional molecules, such as PROTACs (Proteolysis Targeting Chimeras), which recruit E3 ubiquitin ligases to tag the target protein for degradation by the proteasome (Cromm & Crews, 2017; Schreiber, 2024; Tomlinsson et al., 2025).

Notable examples include:

• Lenalidomide: Functions as a molecular glue by recruiting cereblon E3 ligase to degrade transcription factors IKZF1 and IKZF3 in multiple myeloma.
• ARV-110: A PROTAC that targets the androgen receptor for degradation, currently in clinical trials for prostate cancer.

Breakthroughs in medicinal chemistry and structural biology are redefining what’s possible in PPI targeting. Several success stories demonstrate that with the right tools, protein-protein binding can be modulated therapeutically.

Key examples include:

• Venetoclax (Venclexta) and Navitoclax: Bcl-2 inhibitors that restore apoptosis in leukemia cells by disrupting critical PPIs (Kale et al., 2018).
• Idasanutlin: Protein-protein interaction inhibitor of the MDM2-p53 proteins to reactivate tumor suppressor pathways (Scott et al., 2016).
• Maraviroc: An HIV entry inhibitor affecting the CCR5–gp120 interaction.
• Tirofiban: Inhibits the glycoprotein IIb/IIIa receptor, preventing platelet aggregation in cardiovascular diseases (Nada et al., 2024).

DNA-Encoded Libraries (DELs) consist of vast collections of small molecules; each tagged with a unique DNA sequence that serves as a barcode. This technology allows for the simultaneous screening of billions of compounds against a target protein in a single experiment (Goodnow et al., 2017; Favalli et al., 2018; Peterson & Liu, 2023). DELs enable high-throughput, cost-effective identification of novel binders for challenging targets like PPIs.

Advancements in DEL technology have facilitated:

• Rapid Screening: Accelerated identification of lead compounds with high affinity and specificity.
• DELs in Cells: Screening directly inside living cells, providing small-molecule ligands that bind to target proteins in a native cellular environment, enhancing the physiological relevance of the screening process (Petersen et al., 2021).
• Structure-Activity Relationship (SAR) Analysis: Efficient optimization of lead compounds based on binding data.
• Integration with Other Technologies: Combining DELs with techniques like FBDD and computational modeling to enhance drug discovery pipelines (Silvestri et al., 2023).

DELs have been successfully applied in various therapeutic areas:

• Oncology: Identification of protein-protein interaction inhibitors targeting PPIs involved in cancer progression, such as p53-MDM2 and BCL-2 family interactions (Silvestri et al., 2023).
• Neurodegenerative Diseases: Discovery of compounds that modulate PPIs implicated in protein aggregation and neuronal dysfunction (Peterson & Liu, 2023).
• Infectious Diseases: Development of agents that disrupt PPIs essential for pathogen survival and replication (Favalli et al., 2018).

Vipergen offers industry-leading DNA-Encoded Library (DEL) technology designed to accelerate early drug discovery, particularly for challenging targets such as protein-protein interactions (PPIs). At the core of Vipergen’s innovation is the YoctoReactor® platform, which enables the on-DNA synthesis of high-fidelity small-molecule libraries and the efficient identification of potent, selective binders against biologically relevant targets (Blakskjær et al., 2015).

What sets Vipergen apart is its unique ability to conduct DEL screening in living cells, a significant advancement over traditional in vitro assays. Screening in a physiologically relevant environment ensures that identified binders not only engage their target but also retain activity under native cellular conditions. This in-cell screening capability improves the likelihood that hits will translate effectively to functional cellular outcomes, reducing attrition in later stages of drug development. Due to the multiplexing capability of Vipergen’s technology, it can be used for direct discovery of PPI inhibitors. 

By combining robust chemistry, scalable technology, and physiologically meaningful screening conditions, Vipergen’s DEL approach enhances hit quality and therapeutic relevance. These strengths position the company as a key partner for biotech and pharmaceutical companies pursuing next-generation therapeutics, making Vipergen’s Drug Discovery Services particularly suited for identifying hits against PPI targets previously considered undruggable.

Protein-protein interactions represent a vast and largely untapped landscape for therapeutic intervention. Advances like DELs and targeted degradation have transformed early drug discovery approaches. Vipergen is among the leaders making these advances accessible and practical. Learn more at https://www.vipergen.com/services/.

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